Genetic control of sickle red cell dehydration in mice, dehydration accelerates polymerization of deoxy-hemoglobin S, leading to increased cell sickling. The major role in cell dehydration, the K-CI co-transport system and the Ca2+-activated K channel. The activation in sickle cell disease is crucial not only to understand sickle cell dehydration but also to this proposal are 1) to extend the functional characterization of the expressed mouse K-CI cotransporter blood cells and 2) the study of in vivo down-modulation of the K-CI co-transport pathway in transgenic mouse models of sickle cell disease. These objectives will be reached through the accomplishment of the following Specific Aims. Specific Aim 1. Further functional characterization of the mouse K-CI cotransporter (KCC1) and its mutants expressed in Xenopus oocytes. Specific Aim 2. Generation of normal and sickle mice with reduced or absent erythroid KCC1.